SUMMARY/ABSTRACT During the entire course of cortical development neuroepithelial stem cells and later the RG maintain constant cellular contact with meningeal cells lining the surface of the developing cortex. Meningeal fibroblasts generate the basement membrane (BM) covering the cortex, and it has long been known that destruction of the meninges or the BM has substantial consequences for cortical development. We have uncovered evidence that defects in the meningeal developmental program caused by mutation of a transcriptional regulator of meningeal development have major consequences for cortical development by disrupting neuronal migration and progenitor proliferation. These consequences have led us to develop the main hypotheses of this proposal. We believe that 1) the meninges serve a crucial role during cortical development by producing signals regulating neuroepithelial expansion and neuronal migration, and 2) that disruption of this dynamic signaling function leads to major defects in cortical structures. In this proposal I plan to address this hypothesis in three aims that range from anatomic analysis of the brains of mutant mice, to detailed characterization of the cellular mechanism of meningeal-cortical interactions and finally to identify secreted signals produced by the meninges. Aim #1: Evaluate the hypothesis that embryonic defects in meningeal differentiation result in cortical dysplasia. Mice with a new hypomorphic mutation in Foxc1, a meningeally expressed transcription factor, have defects in the differentiation program of the meninges and a cortical dysplasia phenotype. This is associated with defects in radial glial attachment and marginal zone heterotopias and resembles Type 2 Lissencephaly, but also has a distinct developmental profile. This phenotype is dramatically more severe in medial cortical structures at all rostral-caudal levels in the cortex. In this aim, we will examine the developmental anatomic basis for this syndrome using an allelic series of Foxc1 mutants (including our new hypomorphic allele and the previously described null allele) in order to characterize the relationship between meningeal differentiation and cortical organization. Aim #2: Examine how the meninges control cortical progenitor expansion. One of the most exciting phenotypes in the Foxc1 mutant mice is the apparent failure of neuroepithelial progenitors to properly regulate cell cycle exit and switch to producing neurons. In this aim we will characterize this anatomic phenotype in detail in an allelic series of mice with Foxc1 mutations and begin to address potential molecular pathways controlled by meningeal-cortical interactions that control progenitor behavior in early cortical development. Aim #3: Identify Foxc1 dependent, meningeally produced factors regulating progenitor cell expansion. Our evidence thus far supports the idea that the cortical phenotype of the Foxc1 mutants is caused by decreased function of Foxc1 as a transcription factor regulating meningeal differentiation and the expression of signaling molecules by the meninges that control cortical development. We predict that the meninges of Foxc1 mutant mice will fail to produce factors that regulate cortical development. The first goal of this aim is to characterize the cellular mechanism controlled by secreted meningeally produced factors on precursor proliferation using our newly developed in vitro approaches and extend these analysis to dissociated neural precursor cultures. The second goal will be to identify the meningeally expressed factors that regulate cortical progenitor function using a combination of gene expression profiling, fractionation and a candidate gene approach.